Hepatocellular carcinoma (HCC) is an orphan disease in the United States with an estimated incidence of 28,720 cases and prevalence of 35,557 cases in 2012. Most patients with HCC cannot undergo potentially curative treatments such as surgery or transplantation. In patients with advanced disease and for those in whom loco-regional therapy is no longer feasible, sorafenib is the only available FDA approved therapy. This proposal involves the conduct of a first-in-human study of vesicular stomatitis virus with human interferon beta gene insert (VSV-hIFN-B) in patients with advanced HCC who are refractory/intolerant to sorafenib based therapies. The aspects of the proposal are to utilize a recombinant oncolytic vector that has: 1)low prevalence of human infection in the general population to wild type vesicular stomatitis virus (VSV), 2)rapid replication kinetics, 3)inability of VSV to integrate into host genome, 4)broad tropism for mammalian cells, 5)differential sensitivity of tumor cells to VSV due to preponderance of defective type I interferon pathways in tumors and 6) multifaceted mechanism of action including CD4+/CD8+, NK cell mediated anti-tumor activity and direct cytolysis. Insertion of the human interferon beta (hIFN-B) allows for attenuation of the wild type vector and subsequent reduction of risk of neurotoxicity while maintaining anti-tumor efficacy. An added feature to the transgene insert is the potential for CD4+/CD8+ mediated anti-tumor efficacy. Preclinical studies conducted with VSV-hIFN-B by this group and by others with wild type VSV and other VSV constructs have demonstrated anti-tumor activity in both in vitro and in vivo HCC models. This preclinical data formed the basis for this group to conduct formal toxicology studies in rats and Rhesus macaques. A starting dose for first-in-human studies was established in this context (105 TCID50 [Tissue Culture Infective Dose 50]). The current proposal entails the conduct of a first-in-human study of VSV-hIFN-B delivered as single as well as multiple intra-tumoral injections in sorafenib refractory/intolerant patients wit advanced HCC. A 3+3 dose escalation schema will be utilized with 0.6log increments. Objectives for the study include: 1) Determination of the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended Phase 2 dose (RP2D) and observation for evidence of antitumor activity, 2) Assessment of the pharmacokinetic (PK), pharmacodynamic (PD) and biodistribution (BD) properties of the agent will be performed. PK will be assessed by measuring VSV-hIFN-B in blood and tumor serially by reverse transcriptase-polymerase chain reaction (RT-PCR). PD assessments are hIFN-B and VSV antibody detection. BD will entail assessment of VSV-hIFN-B in blood, saliva, feces and urine by RT-PCR and infectious virus recovery with Vero cell assay, and 3) From a translational perspective, immunological assessments entail measuring T cell response, both CD4+ and CD8+ and also innate immune response mediated by NK cells. Given the differential between normal and tumor tissue with regards to ability to mount type I interferon response, the investigators will also measure the transcriptional dynamics of VSV-hIFN-B using serial assessment of whole transcriptome sequencing (RNASeq).